The specific aim of this research is to investigate the acquisition, persistent colonization, and pathogenesis of infection of the respiratory tract by Pseudomonas aeruginosa (p. aeruginosa) in cystic fibrosis (CF). The approach is to use an animal model, developed in this laboratory, for chronic colonization of the respiratory tract by P. aeruginosa. Rats or ferrets will be treated by oral ingestion of Hexamethylphosphoramide (HMPA), a chemical agent which induces microulcerative lesions in the airway epithelium. After two weeks treatment, the animals will be inoculated by transoral intratracheal instillation of P. aeruginosa derived from a sputum sample of a patient with CF. Testing and sampling at two-week intervals after inoculation will be made to characterize: the surface-morphological, histological, and histochemical responses to acquisition and persistent colonization; the growth and distribution of P. aeruginosa; the phagocytic responses of pulmonary macrophages to P. aeruginosa exposed to serum from control and P. colonized animals; the chest radiology and pulmonary function in correlation to the distribution of colonization and pathogenesis; and the influence of submucosal gland responses on colonization and pathogenesis. This investigation is expected to improve the understanding of the pulmonary involvement with P. aeruginosa and to give new insights into the pulmonary defense mechanisms and the effect of impairment of these mechanisms on persistence of colonization. This information is expected to be useful in development of improved methods of therapy and/or prevention of P. aeruginosa colonization and infection in patients with CF.